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Antimicrobial Agents and Chemotherapy, April 2002, p. 1136-1140, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1136-1140.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Comparative In Vitro Activities of Ertapenem (MK-0826) against 469 Less Frequently Identified Anaerobes Isolated from Human Infections

Ellie J. C. Goldstein,^1,2* Diane M. Citron,¹ C. Vreni Merriam,¹ Yumi A. Warren,¹ Kerin L. Tyrrell,¹ and Helen Fernandez¹

R. M. Alden Research Laboratory, Santa Monica-UCLA Medical Center, Santa Monica, California 90404 ,¹ School of Medicine, University of California, Los Angeles, Los Angeles, California 90024²

Received 16 May 2001/ Returned for modification 25 November 2001/ Accepted 26 December 2001

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We studied the in vitro activity of ertapenem against 469 less frequently identified anaerobes from 11 genera and 52 species isolated from human infections. Ertapenem was uniformly active against 460 of 469 (98%) strains at concentrations of 4 µg/ml. Only 4 of 14 Clostridium difficile, 1 of 11 Clostridium innocuum, and 4 of 6 Lactobacillus sp. strains required ertapenem concentrations of 8 µg/ml for inhibition.

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Ertapenem (MK-0826) is a new parenteral carbapenem that is highly resistant to inactivation by a wide variety of beta-lactamases and that has a broad spectrum of antimicrobial activity (2, 3, 8, 9), a half-life of 4.5 h, and a pharmacokinetic profile which allows once-a-day dosing (3, 14). Its activity against the more commonly isolated anaerobic pathogens, such as the Bacteroides fragilis group and Clostridium perfringens, has already been noted (2-4, 16; M. D. Appleman, D. M. Citron, P. N. R. Heseltine, H. Belzberg, A. E. Yellin, J. Murray, and T. V. Berne, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-43, p. 244, 1998). However, scant data exist on this agent's activity against the more recondite anaerobic pathogens that are less frequently identified in clinical specimens. In order to further evaluate ertapenem's full spectrum of anaerobic activity, we determined its comparative in vitro activities against a plethora of anaerobic pathogenic species encountered in human clinical infections.

We studied 469 less frequently identified human clinical anaerobic strains representing 11 genera and 52 species. Isolates were identified by standard criteria (7, 13) and stored in skim milk at -70°C. Isolates were taken from frozen stocks and subcultured twice on brucella agar supplemented with hemin, vitamin K₁, and 5% sheep blood. Susceptibility testing was performed by the reference agar dilution method with supplemented brucella agar according to NCCLS standards (11).

Antimicrobial agents were reconstituted according to the manufacturers' instructions. Serial twofold dilutions were prepared on the day of the test and added to the agar medium. Piperacillin was combined with tazobactam, and this combination was tested with tazobactam at a constant concentration of 4 µg/ml.

The agar plates were inoculated with an inoculum of 10⁵ CFU per spot by use of a Steers replicator (Craft Machine Inc., Chester, Pa.). The plates were incubated in an anaerobic chamber for 44 h at 37°C prior to examination. The MIC was defined as the lowest concentration of an agent that yielded no growth or a marked change in appearance compared to that of the growth on a control plate. Control strains Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741 were included for each drug tested. The numbers and species of isolates tested are given in Table 1.

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TABLE 1 Comparative in vitro activities of ertapenem and seven other agents against 469 unusual anaerobes

Standard laboratory powders were supplied as follows: ertapenem, imipenem, and cefoxitin by Merck & Co., West Point, Pa.; piperacillin and tazobactam by Wyeth-Ayerst, Philadelphia, Pa.; clindamycin by Pharmacia Inc., Kalamazoo, Mich.; metronidazole by Searle Research & Development, Skokie, Ill.; meropenem by Zeneca Pharmaceuticals, Wilmington, Del.; and penicillin G by Sigma Chemical Co., St. Louis, Mo.

The comparative in vitro activities of ertapenem and the seven other agents tested are presented in Table 1. Overall, ertapenem showed excellent activity against the full spectrum of the less frequently identified anaerobic pathogens that we tested. Provisional NCCLS-approved interpretive breakpoints for ertapenem against anaerobes are 4 µg/ml for susceptible, 8 µg/ml for intermediate, and 16 µg/ml for resistant (4). Overall, the in vitro activity of ertapenem was the same as, or within 3 dilutions of, those of piperacillin-tazobactam, imipenem, and meropenem, although some species and strain variabilities were observed. Ertapenem was more active than metronidazole against Actinomyces species, Bacteroides ureolyticus, Campylobacter gracilis, and Anaerobiospirillum species and was highly active against the clindamycin-resistant isolates of various species.

Bacteroides species, including B. capillosus, B. putredinis, B. splanchnicus, and B. tectus, were susceptible to ertapenem, but many were resistant to penicillin G and often required 2 to 8 µg of cefoxitin per ml for inhibition. The MICs at which 90% of organisms were inhibited (MIC₉₀s) by ertapenem were 0.015 µg/ml for Bacteroides ureolyticus and 0.06 µg/ml for Campylobacter gracilis isolates. Similarly, Wexler et al. (16), using the same methodology, found an ertapenem MIC₉₀ of 0.12 µg/ml for 14 isolates of Campylobacter gracilis.

Prevotella species were susceptible to ertapenem, but many of the Prevotella sp. isolates (40 of 77 [52%]) were beta-lactamase producers and were resistant to penicillin G and 5 of 77 (6%) isolates were resistant to clindamycin.

Nine different Clostridium species comprising 96 isolates showed species variation in their susceptibilities to ertapenem. Clostridium innocuum strains required 2 to 8 µg of ertapenem per ml for inhibition, and all 14 Clostridium difficile isolates required 4 to 8 µg/ml for inhibition. Wexler et al. (16) also found ertapenem MIC₉₀s of 8 µg/ml for Clostridium difficile and 1 µg/ml for Clostridium ramosum. In our study, cefoxitin resistance was commonly seen in Clostridium clostridioforme, Clostridium difficile, Clostridium innocuum, and Clostridium ramosum isolates.

Peptostreptococcus spp. were susceptible to ertapenem and all other agents tested. Many of the Lactobacillus strains were less susceptible than the Peptostreptococcus spp. to all agents tested, with an ertapenem MIC₉₀ of >16 µg/ml. Piperacillin-tazobactam and penicillin G were less active against Veillonella spp. than were the three carbapenems and clindamycin (MIC₉₀, 0.25 µg/ml).

In assessing its overall activity against anaerobes, we found that ertapenem appears to inhibit the growth of the majority of both typical and less frequently identified anaerobic pathogens. We previously reported ertapenem's activity against 1,001 anaerobes isolated from human intra-abdominal infections in 17 countries worldwide and found it to be uniformly active against all isolates, including all Bacteroides fragilis group species isolates, with the exception of 12 of 61 (20%) strains of Bilophila wadsworthia, three strains of lactobacilli, and one isolate of Acidaminococcus fermentans (4). Appleman et al. (38th ICAAC) studied the comparative activities of ertapenem against 88 anaerobic isolates obtained from 60 patients with serious intra-abdominal infections and found that ertapenem had "excellent activity" against the 41 Bacteroides fragilis group strains (MIC₉₀, 4 µg/ml). Using the same agar dilution method that we employed, Appleman et al. found 99% of the isolates to be susceptible to both ertapenem and imipenem at MICs of 4µg/ml. Wexler et al. (16) tested ertapenem against 363 anaerobic isolates and found that 98% of the strains were susceptible to ertapenem.

Clinicians must rely on published studies to help guide both empirical therapy as well as specific therapy in situations that involve anaerobes in mixed infections (5, 6). The increasing resistance of many anaerobes to widely used antimicrobial agents (1, 10, 12, 15) underlies a growing need for consistently active antianaerobe agents. Our study, coupled with data from prior studies (4, 16; Appleman et al., 38th ICAAC), suggests that ertapenem offers in vitro activity against a complete spectrum of anaerobic bacterial pathogens that is comparable to or better than that of piperacillin-tazobactam or metronidazole; it was more active than cefoxitin and was active against clindamycin-resistant isolates. Ertapenem is a valuable addition to the armamentarium of antianaerobe drugs.

 
We thank Judee H. Knight and Alice E. Goldstein for various forms of assistance.

This study was funded in part by an educational grant from Merck & Co.

 
* Corresponding author. Mailing address: 2021 Santa Monica Blvd., Suite #740E, Santa Monica, CA 90404. Phone: (310) 315-1511. Fax: (310) 315-3662. E-mail: EJCGMD{at}aol.com.

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Antimicrobial Agents and Chemotherapy, April 2002, p. 1136-1140, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1136-1140.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldstein, E. J. C. Articles by Fernandez, H. Search for Related Content PubMed PubMed Citation Articles by Goldstein, E. J. C. Articles by Fernandez, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Antibiotics Bacterial Infections